The proposed research seeks to better understand the effects of moderate prenatal ethanol exposure in the rat on the agranular insular cortex and related behavioral deficits. The agranular insular cortex is analogous to primate orbitofrontal cortex and is targeted for investigation based on its involvement in a diverse set of behavioral and cognitive processes, including social behaviors and behavioral flexibility, that are among the persistent consequences of prenatal exposure to moderate levels of ethanol. A broad, long-term goal of the proposed work is to understand how prenatal ethanol exposure causes persistent alterations in these behavioral domains with initial emphasis placed on identifying 1) the frontal cortex circuitry involved in specific ethanol-related deficits and 2) the mechanistic bases of fetal-ethanol-related effects within the critical circuitry. The proposed research will evaluate two hypotheses. The first states that prenatal exposure to moderate levels of ethanol exposure causes deficits in behaviors that critically depend upon the agranular insular cortex. The second states that fetal-ethanol-related reductions in glutamatergic receptor density and synaptic transmission in the agranular insular cortex contribute to these deficits. The research plan for evaluating these hypotheses involves four major components: 1) Demonstration of moderate fetal-ethanol-related deficits in social, learning, and motor behaviors that depend on agranular insular cortex, 2) Confirmation that the specific behavioral deficits observed in component 1 critically depend on agranular insular cortex function by demonstrating qualitatively similar deficits following inactivation of agranular insular cortex in non-exposed rats, 3) Quantification of fetal-ethanol-related alterations in the density and function of glutamatergic receptors in agranular insular cortex, and 4) Evaluating behavioral effects of selective, acute manipulations of glutamatergic receptor function in the agranular insular cortex of ethanol-exposed and non-exposed rats. The latter includes evaluating the capacity for disruptions of glutamatergic receptor function in the agranular insular cortex of non- exposed rats to produce behavioral outcomes similar to those observed following prenatal ethanol exposure, and evaluating the capacity of increases in glutamatergic synaptic transmission to modify behavioral deficits in fetal-ethanol-exposed rats. Future studies will expand this approach to include other neurotransmitter systems and brain regions involved in the behaviors of interest. If successful, the findings obtained from this research will enhance our understanding of the biological bases of fetal-ethanol-related behavioral deficits and may contribute to future development of rational, targeted treatment approaches for these deficits. PUBLIC HEALTH RELEVANCE: The proposed research study will evaluate the effects of prenatal exposure to moderate levels of alcohol in the rat on the frontal cortex, and investigate how these effects influence social behavior and learning in adulthood. The primary goal of this research is to link abnormal social behavior and impaired learning following prenatal alcohol exposure to specific regions of the frontal cortex, and to understand how alcohol affects the functions of these brain regions. The data obtained in the proposed research will improve our understanding of how alcohol exposure causes persistent changes in social behavior and learning, and may ultimately contribute to the development of treatments.